Administration Of mCPP Research Articles

Effect of the activation of central 5-HT 2C receptors by the 5-HT 2C agonist mCPP on blood pressure and heart rate in rats

In the present study we investigated the role of central 5-HT 2C receptors in the control of blood pressure and heart rate in non-stressed and stressed, adult, male, Wistar rats. Third ventricle injections of the 5-HT 2C agonist mCPP elicited a significant increase in blood pressure in non-stressed animals. The initial period of this hypertensive response (10–30 min after mCPP administration) was accompanied by baroreflex-mediated bradycardia, while after this period the coexistence of hypertension and tachycardia was observed. These cardiovascular effects promoted by the central administration of mCPP were blocked by pretreatment with the 5-HT 2C antagonist, SDZ SER 082. The administration of SDZ SER 082 alone induced no significant changes in blood pressure or heart rate. The pharmacological stimulation of central 5-HT 2C receptors by mCPP did not change the hypertensive or tachycardic responses induced by restraint stress. Conversely, the blockade of central 5-HT 2C receptors by SDZ SER 082 blunted stress-induced hypertension without modifying stress-induced tachycardia. It is concluded that the activation of central 5-HT 2C receptors induces hypertension in non-stressed rats and that the normal function of these receptors is essential for the rise in blood pressure that occurs in the course of restraint stress.

Modulation of dopamine release by striatal 5‐HT2C receptors

Previous work has demonstrated that dopamine (DA) transmission is regulated by serotonin-2C (5-HT2C) receptors but the site(s) in the brain where these receptors are localized is not known. The present work utilized in vivo microdialysis to investigate the modulation of DA release by 5-HT2C receptors localized in the nerve terminal regions of the mesocortical and nigrostriatal DA pathways. Microdialysis probes implanted in the striatum or the prefrontal cortex (PFC) measured dialysate DA concentrations, while the selective 5-HT2B/2C inverse agonist SB 206553 was given locally by reverse dialysis into these terminal regions. Additionally, the effects of the 5-HT2C agonist mCPP on striatal DA were measured. Local administration of SB 206553 (0.1-100 microM) into the striatum increased DA efflux in a concentration-dependent manner. Systemic administration of mCPP (1.0 mg/kg i.p.) decreased striatal DA and attenuated the SB 206553-induced increase. In contrast, infusion of SB 206553 (0.1-500 microM) by reverse dialysis into the PFC had no significant effect on basal DA efflux in this region. Additionally, high concentrations of SB 206553 had no effect on high potassium (K(+))-stimulated DA release in the PFC. These data contribute to a body of evidence indicating that 5-HT2C receptors inhibit nigrostriatal dopaminergic transmission. In addition, the results suggest that the nigrostriatal system is regulated by 5-HT2C receptors localized in the dorsal striatum. Elucidating the mechanisms by which serotonin (5-HT) modulates striatal and prefrontocortical DA concentrations may lead to improvements in the treatment of diverse syndromes such as schizophrenia, Parkinson's disease, anxiety, drug abuse, and/or depression.

Anxiety-like state associates with taste to produce conditioned taste aversion

The interactions among experience, emotion, and memory are considered to be instrumental in the ontogeny and maintenance of acquired emotional and behavioral disorders (e.g., phobias). Here we address the question whether an anxiety-like state can associate with taste to produce conditioned taste aversion (CTA). We have used an anxiogenic agent, the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP), to induce an anxiety-like emotional state in rats after consumption of an unfamiliar tastant. The anxiogenic agent induced CTA. The mCPP-induced CTA could be prevented by concomitant administration of ethanol, which is known to reverse mCPP-induced anxiety-like behavior, at a concentration that had no effect on CTA memory. In contrast, ethanol did not prevent LiCl-induced CTA. Administration of mCPP before the consumption of the tastant had no effect on the preference for that tastant. Taken together, these results indicate that anxiety-like state can serve as the unconditioned stimulus in CTA training. This finding may be relevant to the ontogeny of pathologies involving food aversion.

Serotonergic Dissection of Obsessive Compulsive Symptoms: A Challenge Study with m-Chlorophenylpiperazine and Sumatriptan

We have conducted a pharmacological challenge experiment in 10 medication-free obsessive compulsive (OC) disorder (OCD) patients. We used a placebo-controlled paradigm for m-chlorophenylpiperazine (mCPP) and sumatriptan challenges. Endocrine, physiological and behavioral variables were assessed at baseline and over a 3-hour period after the challenge. Both cortisol and prolactin were significantly elevated in OCD patients following mCPP administration. Both mCPP and sumatriptan caused significant OC symptom exacerbation with the response to sumatriptan being more robust. We conclude that the 5-HT_1Dβ receptor may play a role in the pathophysiology of OCD.

Differential effects of 5-HT 1 and 5-HT 2 receptor agonists on hindlimb movements in paraplegic mice

The effects induced by serotonergic (5-HT) agonists of the 5-HT 1 and 5-HT 2 subclasses were examined on hindlimb movement generation in adult mice completely spinal cord transected at the low thoracic level. One week postspinalization, intraperitoneal injection (0.5–10 mg/kg) of meta-chlorophenylpiperazine ( m-CPP; 5-HT 2B/2C agonist) or trifluoromethylpiperazine (TFMPP; 5-HT 1B agonist) failed to induce locomotor-like movements. However, dose-dependent nonlocomotor movements were induced in air-stepping condition or on a motor-driven treadmill. In contrast, hindlimb locomotor-like movements were found after the injection of quipazine (5-HT 2A/2C agonist; 1–2 mg/kg). Combined with l-DOPA (50 mg/kg, i.p.), low doses of quipazine but not of m-CPP and TFMPP produced locomotor-like and nonlocomotor movements in air-stepping condition or on the treadmill. Subsequent administration of m-CPP or TFMPP significantly reduced and often completely abolished the hindlimb movements induced by quipazine and l-DOPA. Altogether, these results demonstrate that 5-HT 2A/2C receptor agonists promote locomotion while 5-HT 1B and 5-HT 2B/2C receptor agonists interfere with locomotor genesis in the hindlimbs of complete paraplegic mice. These results suggest that only subsets of spinal 5-HT receptors are specific to locomotor rhythmogenesis and should be activated to successfully induce stepping movements after spinal cord injury.

Central 5-HT 2B/2C and 5-HT 3 receptor stimulation decreases salt intake in sodium-depleted rats

In the present study, we investigated the participation of central 5-HT 2B/2C and 5-HT 3 receptors in the salt intake induced by sodium depletion in Wistar male rats. Sodium depletion was produced by the administration of furosemide associated with a low salt diet. Third ventricle injections of mCPP, a 5-HT 2B/2C agonist, at doses of 80, 160 and 240 nmol, promoted a dose-dependent reduction in salt intake in sodium-depleted rats. The inhibitory effect produced by central administration of mCPP was abolished by the central pretreatment with SDZ SER 082, a 5-HT 2B/2C antagonist. Similar results were obtained with third ventricle injections of m-CPBG (80, 160 and 240 nmol), a selective 5-HT 3 agonist that also induced a dose-related decrease in salt intake in sodium-depleted rats. The central pretreatment with LY-278,584, a selective 5-HT 3 receptor antagonist, was able to impair the salt intake inhibition elicited by third ventricle injections of m-CPBG. Central administration of each one of the antagonists alone or a combination of both antagonists together did not significantly change salt intake after sodium depletion. On the other hand, the central administration of both mCPP and m-CPBG, in the highest dose used to test their effect on salt intake (240 nmol), was unable to modify blood pressure in sodium-depleted rats. It is concluded that: (1) pharmacological activation of central 5-HT 2B/2C and 5-HT 3 receptors diminishes salt intake during sodium depletion, (2) an inhibitory endogenous drive exerted by central 5-HT 2B/2C and 5-HT 3 receptors does not seem to exist and (3) the reduction in salt intake generated by the pharmacological activation of these central receptors is not produced by an acute hypertensive response.

Sleep–wake effects of meta-chlorophenyl piperazine and mianserin in the behaviorally depressed rat

The present study examined the effects of meta-chlorophenyl piperazine (mCPP) and mianserin on the sleep–wake cycle of the clomipramine-induced behaviorally screened depressed rats. Six-hour polygraphic recordings were made between 06:00 and 12:00 h, after a single injection of either saline or mianserin or mCPP into the lateral cerebral ventricle (i.c.v.) of both the depressed ( n=12) and control rats ( n=12). The injection of mCPP in the depressed rats caused a significant reduction in the total duration and number of rapid eye movement (REM) sleep episodes while it increased the REM sleep onset latency compared to the control saline injections. The injection of mianserin in the depressed rats also caused a significant reduction in the total duration and number of REM sleep episodes without changing the REM sleep latency. These results demonstrate for the first time that the central administration of mCPP and mianserin could act as an antidepressant in the clomipramine-induced rat model of depression.

Effect of a 5-HT 2C serotonin agonist, dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs

Stimulation of serotonin receptor subtypes 5-HT 2A or 5-HT 2C in stably transfected 3T3 cells by dexnorfenfluramine (DEXNOR) or serotonin increases secretion of the APP metabolite APP s. It is not known whether activation of these receptors can also affect APP metabolism in vivo. We examined the effects of a single intraperitoneal (i.p.) injection of DEXNOR on APP s levels in cerebrospinal fluid (CSF) of guinea pigs. These levels were significantly ( P<0.05) increased by a single dose of DEXNOR (1–4 mg/kg); those of the APP metabolites Aβ 1–40 and Aβ 1–42 were unaffected. The DEXNOR-induced (1 mg/kg) increases in CSF APP s were suppressed by ritanserin (1 mg/kg) but not by ketanserin (2 mg/kg). When given alone, ritanserin did not affect CSF levels of APP s, Aβ 1–40, or Aβ 1–42. Chronic treatment with DEXNOR for 9 days (1 mg/kg bid, i.p.) increased CSF APP s levels, measured 2 h after the last injection ( P<0.05), and decreased those of CSF Aβ 1–42 ( P<0.05). Neither hippocampal nor cortical levels of the APP holoprotein (APP h), nor body weight, were affected by DEXNOR. Chronic administration of mCPP (1-( m-chlorophenyl)piperazine) (2 mg/kg bid, i.p.), a 5-HT 2B/2C agonist, for 9 days also increased CSF APP s levels ( P<0.5) when measured 2 h after the drug’s last administration; hippocampal and cortical APP h levels were unaffected. However, mCPP also caused a significant decrease in body weight gain. These data indicate that the pharmacological activation of 5-HT 2C receptors can stimulate CSF APP s secretion and reduce Aβ production in vivo. Hence 5-HT 2C receptors, which apparently are localized to the brain, may represent useful targets for the development of treatments for Alzheimer’s disease.

The effects of 5HT(1) agonists on erection in rats in vivo and rabbit corpus cavernosum in vitro.

We have examined the effects of the selective 5-HT(1a) and 5-HT(1b) agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) and 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline (CGS12066b), respectively on erection in rats in vivo and rabbit corpus cavernosum in vitro. Apomorphine (0.1 mg/kg) induced 3.1+/-0.4 erections in vehicle-pretreated animals. At the highest doses tested 8-OHDPAT (0.4-0.64 mg/kg) and CGS12066b (1.0-10.0 mg/kg) significantly reduced apomorphine erection to 0.9+/-0.3 erections and 0.5+/-0.2 erections respectively. The nonselective 5-HT agonist metachlorophenylpiperazine (m-CPP; 0.1 mg/kg) elicited characteristic increases in cavernous nerve activity (CNA) and intracavernous pressure responses (ICP) in anesthetized rats. 8-OHDPAT (0.64 mg/kg) and CGS12066b (1.0 mg/kg) failed to elicit CNA or ICP responses. CGS12066b reduced ICP responses resulting from the direct stimulation of the cavernous nerve whereas 8-OHDPAT did not. CGS12066b reduced the CNA and ICP responses to m-CPP administration whereas 8-OHDPAT potentiated m-CPP induced CNA and ICP responses. In isolated rabbit corpus cavernosum (CC) 8-OHDPAT and CGS12066b both failed to alter noradrenergic induced contraction and non-adrenergic non-cholinergic relaxation. Our results indicate that selective 5-HT(1a) and 5-HT(1b) agonists have different effects in different models of erection.

Central administration of mCPP, a serotonin 5-HT 2B/2C agonist, decreases water intake in rats

In the present study, we investigated in rats the effect of third ventricle injections of 1-(3-chlorophenyl)piperazine ( mCPP), a 5-HT 2 receptor agonist, on water intake induced by three different physiological stimuli: fluid deprivation, acute salt load and hypovolemia. Injections of mCPP in the doses of 80 and 160 nmol/rat were able to decrease water intake in all three conditions studied. Third ventricle injections of mCPP (160 nmol/rat) were no longer able to diminish water intake in the groups of rats pretreated with central injections of an equimolar amount of (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7 H-10-methylindolo[1,7-bc][2,6]-naphthyridine (SDZ SER 082), a selective 5-HT 2B/2C antagonist. The central administration of mCPP (160 nmol/rat) was not able to modify the intake of a 0.1% saccharin solution. It is suggested that the central activation of a 5-HT 2B/2C component is able to impair the drive for water intake induced by the physiological stimuli represented by fluid deprivation, acute salt load and hypovolemia. This effect seems not to be consequent on a general nonspecific central nervous system depression or on a locomotor deficit, because saccharin intake is not affected by third ventricle injections of mCPP.

Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635

The possible role of 5-HT1A and 5-HT2C receptors in the anxiety induced by fear, acute treatment with SSRI antidepressants or the 5-HT receptor agonist m-CPP were tested in the social interaction anxiety test in male Sprague-Dawley rats. Fluoxetine (2.5-10 mg/kg, i.p.), sertraline (15 mg/kg, i.p.) and m-CPP (0.5-2.0 mg/kg, i.p.) all had an anxiogenic-like profile (decrease in time of total social interaction and increase in self-grooming compared to vehicle) under low-light, familiar arena test conditions. All these effects were reversed by pretreatment with the highly subtype-selective 5-HT2C receptor antagonist, SB-242084 at doses of either 0.05 or 0.2 mg/kg, i.p. In contrast, the selective 5-HT1A receptor antagonist WAY-100635 (0.05 and 0.2 mg/kg, s.c.) failed to reverse SSRI-induced decrease in time of total social interaction, further, it augmented self-grooming response. SB-242084 (0.2 mg/kg) and WAY-100635 (0.05 and 0.2 mg/kg) reversed hypolocomotion caused by the SSRI antidepressants. SB-242084, tested alone against vehicle under high-light, unfamiliar arena test conditions associated with fear, caused significant anxiolysis at 0.2 mg/kg and higher doses. These results suggest that increased anxiety in rodents, and possibly, also in humans (e.g. agitation or jitteriness after SSRIs and panic after m-CPP), caused by acute administration of SSRI antidepressants or m-CPP, are mediated by activation of 5-HT2C receptors. Blockade of 5-HT1A autoreceptors may exacerbate certain acute adverse effects of SSRI antidepressants. Both 5-HT1A and 5-HT2C receptors are involved in the SSRI-induced decrease in locomotor activity. In addition, our studies confirm data that subtype-selective 5-HT2C receptor antagonists have strong anxiolytic actions.

The Serotonergic 5-HT2C Agonist m-Chlorophenylpiperazine Increases Weight-Supported Locomotion without Development of Tolerance in Rats with Spinal Transections

The direct serotonergic agonist, m-chlorophenylpiperazine (m-CPP), displays high efficacy at 5-HT2C receptors. Systemic administration of m-CPP increased dramatically the percentage of weight-supported steps made on a treadmill by rats with complete midthoracic spinal transections. The improvement in motor function occurred in rats with grafts of fetal spinal cord into the site of transection (transplant rats) and in spinal rats without grafts (spinal rats). m-CPP produced a therapeutic action with its first administration and after 14 single daily injections. In contrast, the serotonin and norepinephrine reuptake inhibitor, chlorimipramine (CMI), failed to enhance weight support during 21 days of treatment. The results imply that stimulating directly 5-HT2C receptors restores postural support after spinal injury. Thus, 5-HT2C agonists are candidates for treating spinal patients chronically without the development of tolerance.

Increased m-CPP-induced oral dyskinesia after lesion of serotonergic neurons

Peripheral administration of the 5-hydroxytryptamine (5-HT) 2C/1B agonist 1-( m-chlorophenyl)piperazine ( m-CPP) produces abnormal orofacial movements in rats. We have previously shown that this behavior is mediated by 5-HT 2C receptors in the subthalamic nucleus [Neuroscience 72 (1996) 117]. The present studies examined this effect after serotonin depletion to determine whether removal of endogenous serotonin affected this behavioral response and/or subthalamic 5-HT 2C receptors. Rats received an intraventricular infusion of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, 100 mg/10 ml) or vehicle after desipramine pretreatment (25 mg/kg ip). The efficacy of serotonin depletion was confirmed by a decrease in serotonin uptake sites measured by autoradiography. Oral dyskinesia induced by peripheral administration of m-CPP (1.0 mg/kg ip) was markedly increased in lesioned rats compared to sham-operated controls 4 and 8 but not 12 days after the lesion. A subset of lesioned rats that displayed transient seizures after m-CPP injection did not prevent the measurement of oral dyskinesia during the observation period. No differences in 5-HT 2C receptor levels were found with ligand-binding autoradiography in the subthalamic nucleus, or in other brain regions that express this receptor, in rats sacrificed 5 days following 5,7-DHT lesions. The data indicate that lesion of serotonergic neurons in adult rats induces a transient increase in motor responses mediated by subthalamic 5-HT 2C receptors. These data suggest that functional alterations in serotonergic transmission in the subthalamic nucleus may be involved in the pathophysiology of hyperkinetic movement disorders.

Nigrostriatal Lesions Alter Oral Dyskinesia and c-Fos Expression Induced by the Serotonin Agonist 1-(m-Chlorophenyl)piperazine in Adult Rats

The loss of dopaminergic innervation of the basal ganglia, a group of subcortical regions involved in motor control, is the hallmark of Parkinson's disease. The resulting molecular and cellular alterations mediate behavioral deficits and may modify neuronal responses to other neurotransmitters. In the present study, we sought to determine the effects of chronic dopamine (DA) depletion on responses mediated by stimulation of serotonergic 2C (5-HT(2C)) receptors, a serotonergic receptor subtype present in discrete regions of the basal ganglia. Specifically, the effects of unilateral lesions of nigrostriatal DA neurons on oral dyskinesia and Fos protein expression induced by the non-selective 5-HT(2C) agonist 1-(m-chlorophenyl)piperazine (m-CPP) were examined. Confirming previous findings, both peripheral and local injections of m-CPP into the subthalamic nucleus elicited oral dyskinesia. Nigrostriatal lesions markedly enhanced oral bouts induced by peripheral but not intrasubthalamic administration of m-CPP. In intact rats, Fos expression was increased by m-CPP (1 mg/kg, i.p.) in the striatum and the subthalamic nucleus. After nigrostriatal lesions, m-CPP-induced Fos expression remained unchanged in the subthalamic nucleus but was reduced in the medial quadrants of the striatum and was markedly enhanced in the entopeduncular nucleus. These data demonstrate regionally specific alterations in behavioral and cellular responses to a serotonergic agonist in an animal model of Parkinson's disease.

Increased psychological responses and divergent neuroendocrine responses to m-CPP and ipsapirone in patients with panic disorder.

In patients with panic disorder and /or agoraphobia (PDA) an increased sensitivity of central 5-HT2C receptors and a decreased responsiveness of 5-HT1A receptors has been postulated. In the present study, neuroendocrine challenges were performed using oral doses of the non-selective 5-HT2C agonist m-chlorophenylpiperazine (m-CPP) (0.4 mg/kg), the selective 5-HT1A antagonist ipsapirone (0.3 mg/kg), and placebo in 40 patients with PDA and 12 healthy controls in order to compare 5-HT2C and 5-HT1A-specific psychobehavioural and neuroendocrine response patterns. At baseline, all psychobehavioural variables and the plasma concentration of noradrenaline (NE) were significantly increased in the patient group compared to the controls. The administration of m-CPP or ipsapirone was followed by comparable psychological symptoms and, in 55% of all patients, panic attacks. In comparison to the control subjects, patients were characterized by significantly higher psychological reactions to both challenge agents and a significantly higher NE response to m-CPP. In the patient group, there was also a trend towards an increased cortisol response after administration of m-CPP and a decreased cortisol and hypothermia response after administration of ipsapirone compared to the control group. The neuroendocrine findings of our study support earlier reports of opposite changes in the responsiveness of 5-HT2C and 5-HT1A-related receptors in PDA patients. The behavioural hypersensitivity to both, m-CPP and ipsapiron, shows that the provocation of anxiety and other psychological symptoms might be influenced by

Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin(2C/2B) receptor agonists: a combined in vivo electrophysiological and microdialysis study.

Electrophysiological and in vivo microdialysis were used to investigate and compare the effect of tonic activation of serotonin(2C/2B) (5-HT(2C/2B)) receptors on nigrostriatal and mesolimbic dopaminergic (DA) function. Thus, extracellular single unit recordings of neurochemically-identified DA neurons in the SNc and the VTA, as well as simultaneous monitoring of striatal and accumbal DA release were performed following the administration of the unselective 5-HT(2C/2B) agonists, mCPP (m-chlorophenylpiperazine) and MK 212 [6-chloro-2-(1-piperazinyl)piperazine]. Both mCPP (5-320 microg/kg i. v.) and MK 212 (5-320 microg/kg i.v.) dose-dependently decreased the firing rate of VTA DA neurons. The maximal effect was reached at the cumulative dose of 320 microg/kg mCPP and MK 212, which caused a decrease of 42.6 +/- 12.8% and 56.4 +/- 12.6%, respectively. In addition, the total number of events in bursts and the number of bursts of VTA DA cells were significantly reduced by both mCPP and MK 212. On the other hand, mCPP (5-320 microg/kg i.v.) and MK 212 (5-320 microg/kg i.v.) induced a slight decrease in the basal firing rate, but not in bursting activity of SNc DA neurons. Consistent with electrophysiological data, dialysate DA levels in the nucleus accumbens decreased significantly, reaching the maximum of 26.6 +/- 9.6% below baseline levels 120 min after mCPP (1 mg/kg i.p.) administration, and of 25.2 +/- 5.5% 140 min after MK 212 (1 mg/kg i. p.) injection. DA outflow in the striatum was unaffected by both drugs. The inhibitory effect of both mCPP and MK 212 on VTA DA cell activity was blocked completely by pretreatment with the selective 5-HT(2C) antagonist SB 242084 ¿6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline¿ (200 microg/kg), given intravenously 10 min before the first injection of the 5-HT(2C/2B) agonists. SB 242084 (2. 5 mg/kg i.p.) antagonized also the decrease in DA release induced by mCPP and MK 212 in the nucleus accumbens. Taken together, these data indicate that mCPP and MK 212 selectively inhibit mesolimbic dopaminergic function by acting on 5-HT(2C) receptors. Therefore, selective 5-HT(2C) receptor agonists might be useful in clinical conditions where it is necessary to reduce the mesolimbic dopaminergic activity without affecting the nigrostriatal function.

The effect of novel antipsychotics in rat oral Dyskinesia

Rosengarten, Helen, Jack W. Schweitzer and Arnold J. Friedhoff: The Effect of Novel Antipsychotics in Rat Oral Dyskinesia. Prog. Neuro. Psychopharmacol. & Biol. Psychiat 1999, 23, pp. 1389–1404. 1. 1. The effect of the D1 agonist SKF38393 and the 5HT 2 C agonist m-CPP on repetitive jaw movements (RJM) was studied in rats. Acute administration of SKF38393 and/or m-CPP induced RJM in a dose dependent manner. In rats treated with both drugs, RJM responses were about equal to the sum of those obtained with each drug alone. 2. 2. The induction of RJM by SKF38393 was somewhat lower in rats pretreated with 5HT 2C receptor antagonist, mianserin, whereas mianserin severely reduced RJM induced by m-CPP alone. 3. 3. D1 antagonist SCH23390 inhibited SKF38393 induced RJM but had no effect on m-CPP induced chewing behavior. 4. 4. The present study confirms earlier evidence that D1 agonists used at optimal doses for the induction of RJM do not involve the serotonergic system in a significant way. It does, however, implicate the system in the emergence of drug induced oral behavior in rats. 5. 5. The effect of the atypical antipsychotics , clozapine, olanzapine and risperidone was studied on SKF38393 and m-CPP induced RJM. Pretreatment with the atypical antipsychotics clozapine and olanzapine inhibit SKF38393 and m-CPP induced RJM. Pretreatment with risperidone inhibits m- CPP induced oral behavior in rats while increases dose dependently SKF38393 induced RJM.

The pharmacokinetics of phenothiazine neuroleptics during chronic co-administration of carbamazepine: M. Syrek, A. Haduch, J. Wójcikowski, W.A. Daniel. Polish Academy of Sciences, Institute of Pharmacology, Sm [formula omitted]tna 12, 31–343 Kraków, Poland

Rosengarten, Helen, Jack W. Schweitzer and Arnold J. Friedhoff: The Effect of Novel Antipsychotics in Rat Oral Dyskinesia. Prog. Neuro. Psychopharmacol. & Biol. Psychiat 1999, 23, pp. 1389–1404. 1.1. The effect of the D1 agonist SKF38393 and the 5HT2 C agonist m-CPP on repetitive jaw movements (RJM) was studied in rats. Acute administration of SKF38393 and/or m-CPP induced RJM in a dose dependent manner. In rats treated with both drugs, RJM responses were about equal to the sum of those obtained with each drug alone.2.2. The induction of RJM by SKF38393 was somewhat lower in rats pretreated with 5HT2C receptor antagonist, mianserin, whereas mianserin severely reduced RJM induced by m-CPP alone.3.3. D1 antagonist SCH23390 inhibited SKF38393 induced RJM but had no effect on m-CPP induced chewing behavior.4.4. The present study confirms earlier evidence that D1 agonists used at optimal doses for the induction of RJM do not involve the serotonergic system in a significant way. It does, however, implicate the system in the emergence of drug induced oral behavior in rats.5.5. The effect of the atypical antipsychotics , clozapine, olanzapine and risperidone was studied on SKF38393 and m-CPP induced RJM. Pretreatment with the atypical antipsychotics clozapine and olanzapine inhibit SKF38393 and m-CPP induced RJM. Pretreatment with risperidone inhibits m- CPP induced oral behavior in rats while increases dose dependently SKF38393 induced RJM.

Treatment of severe, drug resistant obsessive compulsive disorder with the 5HT 1D agonist sumatriptan

The serotonergic system has been implicated in both the aetiology and pharmacological treatment of obsessive compulsive disorder. In pharmacological challenge tests, mCPP, a 5-HT agonist, with an affinity for 5HT 2C as well as 5HT 1A and 5HT 1D, receptors, was associated with a transient exacerbation of obsessive compulsive symptoms. Chronic administration of mCPP was found to bring about some relief of these symptoms. Sumatriptan is an antimigraine agent, which interacts most potently with 5HT 1D receptors. In the cases to be presented, we report the effects of chronic administration of Sumatriptan to three severe, treatment resistant, OCD patients. Following chronic administration of sumatriptan, these patients, who have been resistant to any former pharmacological treatment, responded with an improvement in their depression and a modest reduction in their obsessive compulsive symptoms.

Acute intravenous administration of ondansetron and m-CPP, alone and in combination, in patients with obsessive–compulsive disorder (OCD): behavioral and biological results

Obsessive–compulsive disorder (OCD) has been linked to abnormal function of brain serotonin (5-HT) pathways. Since ondansetron is a highly selective 5-HT 3 receptor antagonist, the present study was undertaken to investigate 5-HT 3 function in OCD. We administered m-CPP (0.08 mg/kg i.v.) and the potent 5-HT 3 antagonist, ondansetron (0.15 mg/kg i.v.), to 11 OCD patients. All of the subjects received four separate challenges (m-CPP+placebo, m-CPP+ondansetron, ondansetron+placebo and placebo+placebo). In comparison to placebo, administration of m-CPP was associated with significant behavioral effects, particularly self-rated measures of anxiety, altered self-reality, functional deficit and OCD symptoms. Pretreatment with ondansetron did not affect any of the self-rated behavioral symptoms. After administration of m-CPP relative to placebo, significant increases in plasma cortisol and prolactin were found. These changes were not affected by ondansetron. In conclusion, our results do not support the hypotheses that 5-HT 3 receptor-mediated mechanisms modulate m-CPP's behavioral and neuroendocrine effects in patients with OCD.